Fentanyl-containing adhesive preparation for external use

ABSTRACT

Disclosed is a fentanyl-containing adhesive preparation for external use, wherein an adhesive layer is laminated on a supporting body. The adhesive layer contains SIS, a tackifier resin that is composed of a rosin resin and terpene resin, and a softener that is composed of a plybutene and a liquid paraffin. The adhesive layer also contains fentanyl as an active ingredient. The fentanyl-containing adhesive preparation for external use has excellent skin permeation of fentanyl and high preparation stability, without suffering from crystallization of fentanyl during storage.

TECHNICAL FIELD

The present invention relates to a patch containing fentanyl forexternal use which is excellent in permeation of fentanyl through theskin for long term and excellent in preparation-stability withoutsuffering from crystallization of the active ingredient during storage.

BACKGROUND ART

Fentanyl and fentanyl citrate are synthetic narcotic analgesics whichhave been confirmed being about 200 times more potent in analgesicactivity than morphine in animal experiments. Nowadaysfentanyl-containing reservoir-type and long-acting preparations forpercutaneous absorption type are commercially available, for relievingpains due to cancer and said preparations can maintain the bloodconcentration of fentanyl practically at effective levels for 24 to 72hours.

However, such reservoir-type and long-acting preparations forpercutaneous absorption are disadvantageous in that the drug absorptionafter application thereof is fairly slow and the blood concentrationarrives at an effective level only after 12 to 24 hours following theinitial application, so that they cannot produce an immediate analgesiceffect, in that because of their being reservoir-type preparations, theyhave the problem of fluid leakage, and in that they are very strongirritant to the lesion of application due to their containing ethanol.

Attempts have so far been made to produce matrix-type patches forpercutaneous absorption as means for solving the above problems. Forexample, preparations for percutaneous absorption in which an acrylicadhesive is used are commercialized. However, the acrylic adhesive isgenerally inferior in drug-release, causing a problem: namely, a desiredlevel of drug-release can be attained only by increasing the content ofa main drug (Patent Document 1). The increase in the main drug contentcauses other problems, for example the problem of crystallization of themain drug during storage, and the problem of residual fentanyl in thepreparation after application thereof.

On the other hand, while fentanyl-containing patches in which astyrene-isoprene-styrene block copolymer (hereinafter abbreviated as“SIS”) is used as a main base (SIS-based preparations) have also beendisclosed in Patent Documents 2 and 3, there have not yet been developedany patches which can be stored for long term without causingcrystallization and show stable skin adhesiveness and a sufficient maindrug release at the application.

-   [Patent Document 1] Japanese Patent Publication (Tokuhyo) A    2004-524336-   [Patent Document 2] WO 2003/070228-   [Patent Document 3] Japanese Patent Publication A 2008-273865

DISCLOSURE OF INVENTION Problem to be Solved by Invention

Accordingly, it is an object of the present invention to provide a patchcontaining fentanyl for external use which is excellent in permeation offentanyl through the skin, is stored for long term without sufferingfrom crystallization of the active ingredient and fulfills adhesiverequirements.

Means for Solving the Problem

The present inventors made intensive investigations in an attempt tosolve the problems mentioned above and, as a result, found that theabove-mentioned problems can be solved by using a rosin resin and aterpene resin together as a tackifier resin in a patch for external useprepared by adding fentanyl to an adhesive base consisting of a softenerconsisting of a styrene-isoprene-styrene block copolymer, a tackifierresin, and a softener consisting of liquid paraffin and polybutene.

Namely the present invention relates to a patch which is prepared bylaminating an adhesive layer on a support, and in the patch for externaluse prepared by adding fentanyl (1 to 15% by weight per total amount ofthe adhesive layer) to the adhesive layer containing astyrene-isoprene-styrene block copolymer (5 to 50% by weight per totalamount of the adhesive layer), a tackifier resin consisting of a rosinresin and a terpene resin (30 to 60% by weight per total amount of theadhesive layer) and a softener consisting of polybutene and liquidparaffin (5 to 40% by weight per total amount of the adhesive layer),relates to a patch containing fentanyl for external use which ischaracterized in containing a rosin resin (20 to 40% by weight per totalamount of the adhesive layer) and a terpene resin (10 to 30% by weightper total amount of the adhesive layer) as a tackifier resin.

When said rosin resin is especially a hydrogenated rosin glycerol ester,it is possible to obtain the external patch wherein the solubility offentanyl into the preparation, its release-ability and theskin-adhesiveness of the preparation are especially excellent.

By selecting from the range of 0.5:1 to 3:1 the combination ratiobetween liquid paraffin and polybutene as a softener it is also possibleto obtain the external patch which is lower irritant to the skin and iswell balanced in the solubility of the active agent.

EFFECT OF INVENTION

The present invention exerts such an effect as provision of a patchwhich is excellent in permeation of fentanyl through the skin, is storedfor long term without suffering from crystallization of the activeingredient and fulfills adhesive requirements by selecting abovementioned constituents.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 This figure shows results of skin permeation test on hairlessmouse in vitro in Test Example 1.

FIG. 2 This figure shows results of plasma concentration assaying onrabbit carried out in Test Example 4.

BEST MODE FOR CARRYING OUT THE INVENTION

The amount of SIS used in the external patch of the present invention is5 to 50% by weight per total amount of the adhesive layer, preferably 10to 30% by weight per total amount of the adhesive layer.

The tackifier resin gives adhesiveness to the skin by being incorporatedin SIS, and its amount is 30 to 60% by weight per total amount of theadhesive layer, more preferably 40 to 55% by weight per total amount ofthe adhesive layer. When the amount of the tackfier resin is less than30% by weight, the adhesive property as an external patch becomes bad.When the amount is exceed 60% by weight the adhesive tackiness becomestoo strong and when pealing off the patch unfavorablely physicalstimulation occurs.

Furthermore, the tackifier resin used in the external patch of thepresent invention is a mixture of a rosin resin and a terpene resin. Therosin resin includes rosin esters, hydrogenated rosins, glycerin rosinesters, hydrogenated rosin glycerol esters, rosin acids, polymerizedrosins, and the like; among them hydrogenated rosin glycerol esters areparticularly preferred. The amount of the rosin resin is 20 to 40% byweight per total amount of the adhesive layer, more preferably 25 to 35%by weight per total amount of the adhesive layer. When the amount of therosin resin is 20% by weight or less, the solubility of the drug isdecreased and the drug is crystallized and so on to give an unfavorableeffect to the physical property of the preparation. When the amount ofthe rosin resin is 40% by weight or more, the skin permeability of thedrug is decreased.

The amount of the terpene resin is 10 to 30% by weight per total amountof the adhesive layer, more preferably 10 to 25% by weight per totalamount of the adhesive layer. When the amount of the terpene resin is10% by weight or less, the skin permeability of the drug is decreasedand when the amount is 30% or more, the drug is crystallized and so onto give an unfavorable effect to the physical property of thepreparation.

Ratio of the rosin resin and the terpene resin in the present inventionis preferably within the range of 4:1 to 1:1, more preferably 3:1.5 to3:1. When ratio of the rosin resin is beyond 4:1, the skin permeabilityof the drug is decreased and on the contrary, less than 1:1, the drug iscrystallized and so on to give an unfavorable effect to the physicalproperty of the preparation.

The softener is used to improve adaptability to the skin and, further,adjust the tackiness and reduce the physical skin irritation. Thesoftener is selected, in consideration of the solubility of fentanyl andthe effects on the physical characteristics of the preparation, andliquid paraffin and polybutene are especially preferable. The amount ofit is preferably 5 to 40% by weight, more preferably 10 to 30% byweight. When the amount of the softener is less than 5% by weight, theadhesive agent becomes solid. Therefore adhesiveness itself is rapidlyelevated and it causes to skin stimulation and makes adaptability to theskin poor. On the contrary the preparation easily peels off. On theother hand the amount of it is beyond 40% by weight, due to relativedecrease of the amount of a rosin resin, crystallization of the drugoccurs or adhesive power decreases due to decrease of coagulation powerof the adhesive agent and adhesive deposits are unfavorably allowed toremain at the site of application. As for the solubility of fentanyl inliquid paraffin and polybutene, the solubility is higher in polybutenethan in liquid paraffin and the solubility of the main drug in thepreparation can also be adjusted by the level of addition thereof. Ratioof liquid paraffin and polybutene is preferably 0.5:1 to 3:1, morepreferably 1:1 to 2:1. When the proportion of liquid paraffin is higherthan 3:1, the solubility of fentanyl in the preparation decreases andsuch an unfavorable influence as crystallization of the main drug isproduced and, further, the adhesiveness of the preparation to the skindecreases. When ratio of the liquid paraffin is lower than 0.5:1, thetackiness becomes excessively strong and the skin irritation becomesstrong.

An absorption enhancer and the like may be incorporated in the adhesivelayer of the external patch of the present invention in order to promotepercutaneous absorption of fentanyl.

The absorption enhancer includes a higher fatty acid ester such asisopropyl myristate or diisopropyl adipate, a higher fatty acid such asisostearic acid, oleic acid or myristic acid, a surfactant such assorbitan monooleate, polyoxyethylene lauryl ether or monolauric acidpolyethylene glycol, and so on.

An antioxidant may be incorporated in the adhesive layer of the externalpatch of the present invention in order to adjust the stability of themain drug. The antioxidant includes dibutylhydroxy toluene (BHT) orascorbic acid, preferably BHT. The amount of BHT is 0.1 to 5% by weight,preferably 0.5 to 2% by weight.

In the adhesive layer of the external patch of the present invention ifnecessary for adjusting the adhesiveness of the base, ingredients whichare usually used in preparing the patch are suitably selected. Forexample water-absorbing polymer such as polyvinylpyrrolidone orpolyvinylpyrrolidone/vinyl acetate copolymers, inorganic fillers such astitanium dioxide or silica species and so on are suitably used insuitable amount, if necessary.

Fentanyl is incorporated in the adhesive layer according to the presentinvention preferably in an amount of 0.1 to 15% by weight, morepreferably 1 to 12% by weight, further more preferably 3 to 10% byweight.

The thickness of the adhesive layer according to the present inventionis not particularly restricted; however, when the layer is too thin, theadhesive power decreases and, when it is too thick, the amount of thedrug remaining unutilized in the preparation increases, the costincreases and the preparation becomes easily peelable upon rubbingagainst clothing; therefore, the thickness in question is desirably 20to 100 μm.

Generally, it has been revealed that the flexibility and stretchabilityof a backing in the patch influence the adaptability to the skin andgreatly contribute to improved percutaneous drug absorption. Therefore,the backing having high flexibility and stretchability is used in thepatch according to the present invention as well and, as such backing,there may be mentioned a low-density polymer film, a nonwoven fabric, awoven fabric, and the like; from the viewpoints of general versatilityand economy, among others, a polyethylene terephthalate film isdesirable. Thickness of the film is desirably 0.1 to 100 μm. When thethickness is in excess of 100 μm, the patch can no longer adapt to orfollow the unevenness and/or motion of the skin due to the stiffness ofthe polyethylene terephthalate film, with the result that thepercutaneous absorption of the drug decreases.

The release liner used in the present invention includes polyethyleneterephthalate, polypropylene, paper, and the like. The release liner issilicone-treated for optimizing the release force, if necessary.

The patch according to the present invention can be prepared, forexample, in the following manner.

The base, including the tackifier, is dissolved in an organic solvent,for example toluene, and then agitated and mixed with other ingredientsdissolved in an appropriate organic solvent. The obtained solution isapplied onto a silicone-treated release liner, followed by 10 minutes ofdrying at 90° C. to fowl an adhesive layer with a thickness of 20 to 100μm. The obtained adhesive layer is laminated on a polyethyleneterephthalate film, followed by cutting to an appropriate size andshape, whereby the percutaneous absorption preparation according to thepresent invention can be obtained.

EXAMPLES

The following examples illustrate the present invention morespecifically. They, however, by no means limit the scope of the presentinvention. In the examples, “part(s)” means “part(s) by weight”, unlessotherwise specified.

Examples 1 to 11

According to the formulations given in Tables 1 and 2, respectivepatches for external use of Examples were produced.

TABLE 1 Exam- Exam- Ingredient Example 1 Example 2 ple 3 Example 4 ple 5Styrene- 16 16 16 16 16 isoprene-styrene block copolymer Hydrogenated 3030 30 30 30 rosin glycerol ester Terpene resin 20 20 20 20 20 Polybutene10 10 10 10 10 Liquid paraffin 14.5 16 17.5 14 12.5 BHT 0.5 0.5 0.5 0.50.5 Monolauric acid 0.5 polyethylene glycol Isostearic acid 2 Fentanyl 97.5 6 9 9 Total 100 100 100 100 100

TABLE 2 Exam- Exam- Exam- Exam- Exam- Exam- ple ple ple ple ple pleIngredient 6 7 8 9 10 11 Styrene- 20 20 16 16 16 16 isoprene- styreneblock copolymer Hydrogenated 30 30 30 30 30 30 rosin glycerol esterTerpene resin 30 30 18 18 20 20 Polybutene 3 8 8 18 10 10 Liquidparaffin 9 4 20 10 15.5 14.5 BHT 0.5 0.5 0.5 0.5 1.0 2.0 Fentanyl 7.57.5 7.5 7.5 7.5 7.5

Comparative Examples 1-9

According to the formulations given in Tables 3 and 4, respectivepatches for external use of Comparative examples were produced.

TABLE 3 Comp. Comp. Comp. Comp. Comp. Ingredient ex. 1 ex. 2 ex. 3 ex. 4ex. 5 Styrene-isoprene-styrene 16 16 15 25 15 block copolymerPolyisobutylene 10 10 Hydrogenated rosin 50 15 8 15 glycerol esterTerpene resin 50 Alicyclic petroleum resin 15 32 15 Polybutene 10 10Liquid paraffin 14.5 14.5 31.5 26.5 29.5 Ammonium chloride 1 1 1 Oleylalcohol 3 3 Dipropylene glycol 2 2 BHT 0.5 0.5 L-Menthol 2 Fentanyl 9 97.5 7.5 7.5 Total 100 100 100 100 100

Comparative example 3: was prepared referring to Example 1 inWO2003/070228.

Comparative example 4: was prepared referring to Example 9 inWO2003/070228.

Comparative example 5: was prepared referring to Example 10 inWO2003/070228.

TABLE 4 Comp. Comp. Comp. Comp. Ingredient ex. 6 ex. 7 ex. 8 ex. 9*Styrene-isoprene-styrene 29 16 28 16 block copolymer Hydrogenated rosinglycerol 30 20 30 20 ester Terpene resin 30 11 30 11 Polybutene 0.5 10 335 Liquid paraffin 2.5 35 1 10 BHT 0.5 0.5 0.5 0.5 Fentanyl 7.5 7.5 7.57.5 Total 100 100 100 100 *Physical property of Comparative example 9was too bad to prepare a formulation.

Test 1: Skin Penetration on Hairless Mouse in Vitro

The patches of Examples 1 and Comparative examples 1 were subjected tohairless mouse skin penetration test for fentanyl-release in vitro.

A skin segment excised from the mouse back was set on a Franz cell, thecell was filled with phosphate-buffered saline, and warm water at 37° C.was circulated through the water jacket. A circular sample (16 mm indiameter) was punched out from each preparation and applied to theexcised skin, the receptor solution was sampled with time, the amount offentanyl that had permeated was determined by liquid chromatography, andpermeation rate was calculated. The result is shown in FIG. 1.

Test 2: Stability

The preparations of Examples 1 to 9 and Comparative example 1 to 8 after2 months of storage at room temperature were subjected to appearanceobservation by visual inspection; the results are shown in Table 5. Thepreparations showing precipitation of crystal were evaluated as “X” andthe preparations showing no precipitation of crystal as “◯”.

TABLE 5 Sample Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. 1 2 3 4 5 6 7 8 9Observa- ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ tion result Sample Comp. Ex. 1 Comp. Ex. 2Comp. Ex. 3 Comp. Ex. 4 Observa- ∘ x x x tion result Sample Comp. Ex. 5Comp. Ex. 6 Comp. Ex. 7 Comp. Ex. 8 Observa- ∘ ∘ x ∘ tion result

Test 3: Adhesiveness

The preparations of Examples 1, 6 to 9, and Comparative examples 3 to 8were each subjected to 180° peeling-off test using a tensile tester(Rheometer CR500DX, product of Sun Scientific Co., Ltd.) to evaluate theadhesiveness. The results thus obtained are shown in Table 6.

TABLE 6 Sample Ex. 1 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Adhesive- 6.4 8.4 9.8 3.03.6 ness (N) Sample Comp. Comp. Comp. Comp. Comp. Comp. ex. 3 ex. 4 ex.5 ex. 6 ex. 7 ex. 8 Adhesive- 0.2 1.0 0.2 13.2 0.5 13.9 ness (N)

Discussion

-   (1) The results shown in Tables 5 to 6 revealed that external    patches of the present invention are excellent in drug-release,    stability and adhesiveness. On the other hand, it is revealed that    the patches of Comparative examples 1 is inferior to the present    invention in the main drug -release, patches of Comparative examples    2, 3, 4 and 7 have a trouble in crystallization of the main drug in    the preparation and patches of Comparative examples 3 to 5, and 7    are considerably inferior in adhesiveness comparing to the present    invention. Furthermore patches of Comparative examples 6 and 8 have    much higher adhesiveness comparing with the present invention and    therefore it is afraid for skin irritation on them.

Test 4: Rabbit Plasma Concentration

The patch of Example 1 and a commercialized product (a reservoir-typepatch containing fentanyl dissolved in ethanol) were subjected tomeasurement on rabbit serum concentration of fentanyl (each dose being4.2 mg). Each patch was applied to the depilated rabbit back for 72hours, and blood samples were taken with time and subjected to liquidchromatography/mass spectrum method (LC/MS) for plasma fentanylconcentration determination. The results thus obtained are shown in FIG.2. It was revealed that the patch of the present invention shows quickincrease of fentanyl-serum concentration comparing with thecommercialized product and maintain higher serum concentration offentanyl for long term.

INDUSTRIAL APPLICABILITY

The fentanyl-containing patch for external use of the present inventionhas excellent permeation of fentanyl through the skin for long term,high preparation-stability during storage without sufferingcrystallization of the active substance, and can be used for relievingpain in cancer patients, and the like.

1. A fentanyl-containing patch for external use prepared by adding fentanyl as an active ingredient to the adhesive layer containing 5 to 50% by weight per total amount of the adhesive layer of a styrene-isoprene-styrene block copolymer, 30 to 60% by weight per total amount of the adhesive layer of a tackifier resin consisting of a rosin resin and a terpene resin and 5 to 40% by weight per total amount of the adhesive layer of a softener consisting of polybutene and liquid paraffin.
 2. The fentanyl-containing patch for external use according to claim 1 wherein the amount of the rosin resin is 20 to 40% by weight per total amount of the adhesive layer and the amount of the terpene resin is 10 to 30% by weight per total amount of the adhesive layer.
 3. The fentanyl-containing patch for external use according to claim 1 wherein the rosin resin is hydrogenated rosin glycerol ester. 